Diffusion Nuclear Magnetic Resonance (NMR) has been used for over 40 years to determine self-diffusion coefficients, which may be interpreted in terms of aggregate size, permeability of the medium through which the molecules are moving, and binding events occurring between the diffusing species and larger molecules or the porous matrix. The most common diffusion NMR techniques rely on a diffusion encoding block comprising pairs of magnetic field gradient pulses to label the NMR radio frequency signal for displacements occurring during the time between the pulses. Diffusion NMR techniques and methods of analysis are not only applied in vitro but also in the context of medical magnetic resonance imaging (MRI) for the detection of pathological conditions such as ischemic stroke, demyelinization disorder, and tumours. In some cases, especially for stroke, image contrast based on diffusion is more informative than the more classical modes of contrast based on the nuclear relaxation rates R1 and R2.
The rate of water exchange between compartments with different relaxation/diffusion characteristics is a potential useful marker for pathological conditions in tissue. Diffusion NMR experiments performed as a function of the diffusion can be analyzed with the Kärger model to estimate the rate of exchange (Kärger, J., H. Pfeifer, and W. Heink. 1988. Principles and applications of self-diffusion measurements by nuclear magnetic resonance. Adv. Magn. Reson. 12:1-89). The analysis is hampered by the weak dependence of the NMR signal on the exchange rate.
The publications P. T. Callaghan, and I. Furó, Diffusion-diffusion correlation and exchange as a signature for local order and dynamics. J. Chem. Phys. 120 (2004) 4032-4038 and K. E. Washburn, and P. T. Callaghan, Tracking pore to pore exchange using relaxation exchange spectroscopy. Phys. Rev. Lett 97 (2006) 175502. discloses two-dimensional nuclear magnetic resonance experiments for the examination of exchange processes. The methods, known as diffusion exchange spectroscopy and relaxation exchange spectroscopy, employ two independently incremented relaxation/diffusion weighting blocks separated by a mixing time, and signal analysis using two-dimensional inverse Laplace transformation. However, a serious drawback is the inordinate demands on instrument time for acquiring the large amount of data required for the two-dimensional inverse Laplace analysis, thus making the method impractical for studies of human subjects with limited patience.
In summary, up until now the currently available diffusion NMR methods for estimating exchange rates are either very time consuming (Callaghan) or rely on curve-fitting with only weak dependence between the estimated parameters and the information in the experimental data (Kärger). Other known methods that could be used to obtain the exchange times are invasive methods, such as observations of the diffusion of a marker molecule by means of light scattering, microscopy, absorption spectroscopy and X-ray. This is not only difficult to use in vivo due to the toxicology risks but one could never assure that the tissue and body fluids are unaffected by the introduced marker.
However, the PCT application WO2008/147326 discloses a method which solves the problems disclosed above. The method according to the PCT application WO2008/147326 comprises emitting a radio frequency pulse sequence towards an object being subjected to a magnetic field, wherein said object comprises a molecule having an atom with a nuclear spin differing from 0, emitting a gradient pulse sequence towards said object, detecting a magnetic resonance signal from said object corresponding to said emitted radio frequency pulse sequence, and processing said magnetic resonance signal.
Moreover, the method according to the PCT application WO2008/147326 is characterized in that said gradient pulse sequence comprises a filter block (first diffusion weighting block) configured to reduce at least a part of the distribution of diffusion coefficients of said object, and a diffusion encoding block (a second diffusion weighting block) occurring at a predetermined time after emitting said filter block, and said processing comprising comparing a portion of said magnetic resonance signal with a portion of a predetermined magnetic resonance signal, resulting in a compared signal, wherein the portion of said predetermined magnetic resonance signal is either user defined or resulting from a previously applied gradient pulse sequence.
The method according to the PCT application WO2008/147326 has several advantages. The general solution according to invention of the PCT application WO2008/147326 is that it utilizes a sequence of gradient pulses as a filter on a diffusion experiment. Thereby identical molecules can be analyzed separately and differentiated based on how restricted their diffusion is. The rate of exchange between various compartments is an important parameter that is obtainable utilizing the present invention according to some specific embodiments. Moreover, the invention according to the PCT application WO2008/147326 offers a new contrast mode for MRI studies of materials, such as tissue, where the exchange rate varies as a function of position.
Furthermore, other advantages with the invention according to the PCT application WO2008/147326 are shortened overall experiment time duration needed, which as such enables the invention to be used in vivo, e.g. such as a means for contrast in Magnetic Resonance Imaging (MRI), in some cases the non-existing need for background information from other experiments, such as the shape or diffusion coefficient of the studied molecule, in order to obtain a reliable exchange rate result, and the possibility of giving an image where the contrast is dependent on differences in exchange rate.
However, there also exist problems with the method and the protocols disclosed in the PCT application WO2008/147326 and with Callaghan's protocol.
One such problem is the fact that these protocols are not applicable on all MRI instruments. Some of the standard MRI scanners used today cannot acquire enough data to allow for e.g. a method according to WO2008/147326 to be applied, such as for a global two component fit or ILT analysis.
Another problem with clinical MRI is the in general high noise levels. Due to the large data acquisition according to WO2008/147326, noise may in fact be a large problem.
One object of the present invention is to provide a method for MRI, which method is applicable to a very wide range of MRI scanners, such as the standard clinical whole-body MRI scanners used today. Another object of the present invention is to provide a method for MRI which is not largely affected by noise.